Rates of depression in multiple sclerosis (MS) have been estimated at between 14% and 54%, and have been shown to be higher than rates in the general population or in other chronic illnesses. While untreated depression in MS is likely to worsen over time, it has been shown to respond well to treatment with cognitive behavioral therapy (CBT). Nevertheless, many patients with MS remain untreated. This may be due in part to common symptoms of MS, which can interfere with regular office visits. We are proposing to test a model of CBT, administered over the telephone, designed to treat depression in MS. While the use of telephone counseling and support services is increasing, empirical evidence on the efficacy of such services for the treatment of depression is scant at best. A patient workbook and therapist CBT treatment manual were developed by the PI and tested in an uncontrolled pilot study. In the 8-week pilot, 32 MS patients were randomly assigned to either telephone CBT or standard care (SC) in an HMO. Patients receiving telephone CBT showed improvement, as compared to patients receiving SC as measured by the Profile of Mood States Depression-Dejection scale (p=.01). This study proposed to enroll 128 patients in a randomized treatment study. Patients will be selected from the diverse population of patients in the Northern California Kaiser Permanente Medical Care Group (KPMC). Patients who meet inclusion criteria, including definite MS, activity limitation (disability) criteria, and DSM-IV diagnosis of Major Depressive Disorder (MDD), will be randomized into one of two treatment groups: 1) Coping with MS (CMS) telephone psychotherapy, which is a 16 week, 18 session, manualized form of telephone CBT that focuses on depression and adjustment to illness; or 2) a non-directive (ND) therapy contrast condition that controls for the nonspecific effects of psychotherapy. Outcomes include dichotomous and continuous measures of MDD, Quality of Life, and activity limitations. Patients will be followed for one year after the end of treatment. If the treatment proves efficacious, it will result in a validated form of telephone CBT for the treatment of depression that can be provided to MS patients independent of their mobility status or geographic location.